A percutaneous transluminal angioplasty (PTA) of blood vessels, including the coronary arteries (PTCA), is a very common procedure to reduce vessel narrowing (i.e., stenosis) that obstructs blood flow to tissue, especially human organs. The angioplasty procedure typically involves inflating a balloon within the constricted region of the blood vessel so as to re-open the blood vessel. The success rates of coronary angioplasty procedures are typically inversely related to (i) the extent of the vascular disease, and (ii) the patient's intolerance to myocardial ischemia (i.e., blood flow obstruction) during the temporary blood vessel occlusion which is associated with a PTA procedure.
More particularly, one of the principle limitations of a coronary angioplasty procedure is the complete obstruction of blood flow during the inflation of the angioplasty balloon. After a short period of balloon occlusion, patients experience myocardial ischemia due to the interruption of oxygenated blood to the myocardium. Myocardial ischemia is usually indicated by angina pectoris and/or cardiac arrhythmias.
In the past, several perfusion balloon catheters have been developed to overcome the problem of total blood flow obstruction during percutaneous coronary interventions. By way of example but not limitation, U.S. Pat. No. 4,944,745 (Sograd) discloses a perfusion balloon catheter that allows passive perfusion of blood through a catheter whose balloon is obstructing blood flow. U.S. Pat. No. 4,909,252 (Goldberger) discloses a perfusion balloon catheter with a central opening which allows blood flow through the catheter when the balloon is fully inflated. U.S. Pat. No. 5,087,247 (Horn et al.) discloses a balloon perfusion catheter with an elongated flexible perfusion shaft, with multiple openings proximal and distal to the balloon, in order to permit blood flow through an artery during balloon inflation. International Patent Publication No. WO 9732626 (Cox et al.) discloses an inflatable balloon envelope allowing blood passage during inflation of the device.
While such perfusion balloon catheters permit some continued blood flow while their balloons are inflated, they are nonetheless limited to a flow rate which is something less than the normal flow rate of the blood passing through the vessel. In other words, perfusion balloon catheters can provide, at best, only some fraction of the normal flow rate which existed in the blood vessel prior to insertion of the catheter and inflation of the balloon. Thus, when perfusion balloon catheters are placed into relatively small arteries (e.g., the coronary arteries) which already have modest flow rates, the further reduction of an already-low flow rate is frequently clinically unacceptable. The inadequacies of the perfusion balloon catheter were characterized in a publication by Ferrari et al. (Coronary Artery Disease, 1997) who conclude their studies with the statement that in “high-risk patients dependent on adequate coronary perfusion, autoperfusion balloons are not able to provide sufficient distal coronary blood flow during balloon inflation”.
Insufficient blood flow distal to an inflated balloon causes ischemia and hence hypoxia (i.e., oxygen deprivation) in tissue (e.g., the end organs) because the oxygenation of tissue previously supplied with blood is reduced.
For this reason, angioplasty in the coronary arteries is a relatively high risk procedure in patients who require dilatation of the unprotected trunk of the left main coronary artery. Tan et al. (Circulation, 2001) concluded that although percutaneous balloon interventions are a generally accepted treatment modality for coronary artery disease, left main PTCA procedures remain a high risk procedure for the patient.
Another limitation of a coronary angioplasty is restenosis. Restenosis after a PTCA procedure has been successfully inhibited by ionizing radiation therapy (i.e., brachytherapy) applied prior to, or shortly after, angioplasty. Thus, vascular brachytherapy using radioactive sources has become a new treatment option to prevent restenosis. More particularly, radioactive stents disclosed in U.S. Pat. No. 5,059,166 (Fischell et al.) and/or radioactive catheters disclosed in U.S. Pat. No. 5,199,939 (Dake et al.) have been used to minimize or eliminate neointimal hyperplasia after angioplasty. However, the logistical complexities of using radiation sources in coronary arteries, and radiation safety issues, have prompted researchers to improve the irradiation technology. To this end, U.S. Pat. No. 5,951,458 (Hastings et al.) discloses a radiation catheter that releases oxidizing agents such as H2O2 to prevent restenosis after a cardiovascular intervention. The method described by Hastings et al. helps to reduce the radiation doses, or treatment times, necessary to prevent restenosis.
Oxygenated perfluorocarbon (PFC) emulsions have been used to treat ischemic and hypoxic disorders. Oxygen-transferable PFC emulsions became known as artificial blood substitutes more than twenty years ago. By way of example but not limitation, in U.S. Pat. No. 3,958,014 (Watanabe et al.) and U.S. Pat. No. 4,252,827 (Yokoyama et al.), perfluorocarbon (PFC) emulsions are disclosed that have a small PFC “particle” size of 0.02 microns to 0.25 microns, and which were injected into the bloodstream. Additionally, U.S. Pat. No. 4,445,500 (Osterholm) teaches that oxygenated perfluorocarbon (PFC) emulsions can be injected into the cerebrospinal pathway to improve aerobic respiration of tissue. Furthermore, U.S. Pat. No. 4,795,423 (Osterholm) discloses an intraocular perfusion with perfluorinated substances to treat ischemic retinopathy.
Unfortunately, clinical experience has shown that the current approaches for using PFCs to oxygenate tissue are highly problematic. More particularly, and as will hereinafter be discussed in further detail, the current approaches for using perfluorocarbons (PFCs) prevent the use of “pure” PFC solutions and, instead, require the use of PFC emulsions. These emulsions themselves introduce a whole new set of problems which effectively limit the clinical use of PFCs in the bloodstream.
More particularly, it has been found that a pure perfluorocarbon (PFC) solution, with or without a “passenger” gas (e.g., oxygen), cannot be safely injected directly into the arterial or venous bloodstream, e.g., using a standard intravenous (IV) line or syringe. This is because introducing pure PFC solutions in this manner creates dangerous (and potentially fatal) embolisms in the bloodstream. These embolisms are created due to the fact that the PFCs are hydrophobic and are not soluble in blood. Thus, when a pure PFC solution is injected directly into the bloodstream (e.g., for hyperoxic medical therapy), the PFC tends to aggregate into relatively large bodies (or “particles”) within the bloodstream. These relatively large aggregations of PFC tend to create embolisms in the bloodstream. For this reason, introducing pure PFCs (with or without a “passenger” gas) directly into the bloodstream, without the provision of some sort of PFC-dispersing mechanism, is not feasible due to the creation of dangerous embolisms.
Furthermore, it is not possible to eliminate the problematic PFC aggregations by simply diluting the PFC with another liquid prior to its introduction into the bloodstream, because the PFCs are not easily soluble in biocompatible fluids (e.g., the PFCs are insoluble in saline). Thus, the PFC tends to re-aggregate even when it is diluted with another liquid, so that the problematic PFC aggregations remain.
As a result, and as noted above, emulsifying agents (such as egg yolk, phospholipids, Pluronic-F68 and other emulsifiers) have been added to the PFC prior to the injection of the PFC into the bloodstream, whereby to “break up” the PFC particles and minimize aggregations of the PFC within the bloodstream. See, for example, U.S. Pat. Nos. 3,958,014 (Watanabe et al.), 4,252,827 (Yokoyama et al.), 4,445,500 (Osterholm) and 4,795,423 (Osterholm). Thus, with the prior art approach, emulsifying agents are used as a PFC-dispersing mechanism to break up the PFC and prevent the problematic PFC aggregations which can lead to embolisms.
However, clinical studies in humans evaluating such PFC emulsions (e.g., Fluosol and others) have shown that the use of these emulsions, infused into blood with the PFC for hyperoxic therapy, can cause respiratory insufficiency and pulmonary edema (Wall T C et al., Circulation 1994), most likely due to fluid overload and subsequent congestive heart failure. Thus, PFC emulsions can be considered as PFC “particles” (i.e., aggregations) that are accompanied by large quantities of another therapeutic agent (i.e., the emulsifier) which serves to emulsify (i.e., disperse) the pure PFC within the bloodstream. However, these large quantities of additional therapeutic agent (i.e., the emulsifier) in turn significantly increase intravascular volumes and thereby induce unwanted side effects such as respiratory insufficiency and pulmonary edema.
In addition, PFC emulsions are capable of uploading and releasing, per unit of volume, far less oxygen than a pure PFC solution. Thus, where emulsions are added to the PFC in order to avoid the creation of embolisms, it is generally necessary to provide additional systemic oxygenation to the patient via the lung (e.g., by breathing 100% oxygen) so as to create a sufficiently therapeutic oxygen tension of the PFC emulsions (Kim H W et al., Artificial Organs, Vol. 28, No. 9 2004). However, such intensive systemic oxygenation is normally to be avoided clinically, due to the adverse affects of elevated oxygen concentration on the lungs (e.g., oxygen toxicity) (Kim H W et al., Artificial Organs, Vol. 28, No. 9 2004).
Moreover, the use of emulsions to disperse the PFC in blood can also cause allergic reactions in the patient. Mattrey et al. showed that PFC emulsions can cause allergic reactions (Mattrey R F et al., Radiology 1987). More particularly, in an investigation of Fluosol-DA 20% as a contrast agent using Pluoronic-F68 and others as emulsifiers for PFC in humans, it was reported that Fluosol-DA 20% caused allergic reactions which are most likely triggered by complement activation of the substance Pluoronic-F68 (Mattrey R F et al., Radiology 1987). Since pure PFCs are chemically inert and contain no emulsifiers, no allergic reactions are to be expected when using pure PFCs in the blood; thus it has been concluded that it is the presence the emulsifiers which trigger the allergic reaction in the patient.
For these reasons, using oxygenated PFCs in conjunction with emulsifiers to prevent hypoxia has not heretofore been clinically successful.
Thus it will be seen that pure PFCs (with or without a “passenger” gas) cannot be introduced directly into the bloodstream without also providing some PFC-dispersing mechanism to prevent embolisms. However, it will also be seen that the prior art approach of using emulsions as the PFC-dispersing mechanism for the PFC introduces a whole new set of problems which effectively limit the clinical use of PFCs in the bloodstream.
For these reasons, prior art PFC systems for delivering oxygen to tissue have not heretofore been clinically successful.